|Grade||Level of Evidence|
|A||Multiple double-blind, controlled clinical trials.|
|B||1 double-blind, controlled clinical trial.|
|C||At least 1 controlled or comparative clinical trial.|
|D||Uncontrolled, observational, animal or in-vitro studies only.|
|Grade||Effect||Size of Effect||Comments|
Dietary supplementation increased wound strength in rats, but seems to be limited to the initial phase of wound repair.
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Table of contents:
Retinyl acetate is the acetate ester of retinol. It is chemically synthesized from retinol by treatment with acetic anhydride or acetyl chloride in pyridine, or from acetylated intermediates in the synthesis of retinol. It can also be produced by metabolically engineered E. coli in a 2-phase culture system, along with other retinoids such as retinol and retinal.
Like retinyl palmitate, retinyl acetate is often used in cosmetic products because of its superior thermal stability over retinol. It does however decompose under photoirradiation, forming isomers of anhydroretinol. The photostability of retinyl acetate can be improved by encapsulating it in nanoparticles made of UV absorptive chitosan.
There is evidence that retinyl acetate penetrates the skin and is metabolized to the active forms of vitamin A. Its absence in the effluent in an experiment done on the rabbit ear suggested that it was not absorbed, but it has been shown to permeate, albeit slowly, through reconstructed human epidermis. Experiments on pig ear skin also revealed low amounts of retinyl acetate in the dermis and epidermis following topical application. 
Human epithelial cells have the capacity to convert retinyl acetate to retinol in vitro, through the action of a cellular hydrolase. Likewise, retinyl acetate applied to pig ear skin has been found to be accompanied by retinol in the stratum corneum and epidermis, providing evidence of enzymatic hydrolysis of the ester.
Several techniques may be employed to optimize the release, permeation and retention of retinyl acetate in the skin. Lemon essential oil enhances the transepidermal release of retinyl acetate from topical emulsions by 5.8 times. Encapsulation of retinyl acetate in nanoparticles on the other hand seems to significantly slow its absorption rate, but results in retention of retinyl acetate in the hair follicles, through which retinyl acetate can diffuse into the dermis.
3. Effects on the skin
3.1 Age-related improvements
In vitro,retinyl acetate dose-dependently increased the biosynthesis of sulfated glycosaminoglycans, important components of the extracellular matrix in dermal and epidermal mouse cells and is also known to influence epidermal proliferation and differentiation.
A single-center, controlled-use study of a test cream containing 12% gluconolactone + 1% retinyl acetate revealed improvements in several photoaging parameters including fine lines, coarse wrinkles and skin thickness after 12 weeks, though it was not possible to ascertain whether these effects were due to retinyl acetate.
3.2 Wound healing
Dietary supplementation of retinyl acetate to male rats with marginal vitamin A status has been demonstrated to lead to a mild increase in postmortem wound tensile strength in the initial but not the secondary phase of wound repair.
4. Side Effects
4.1 Contact allergy and dermatitis
Mice fed retinyl acetate-enriched diets have enhanced contact sensitization, which can lead to allergic contact dermatitis. In fact, there has been 1 case report of a 44-year-old male who developed eczema while employed in a a job involving drying, sieving and packing retinyl acetate. The eczema cleared after the patient changed jobs, and patch testing revealed allergic reactions to retinyl acetate.
It therefore appears plausible that topical use of cosmetic products containing retinyl acetate may cause contact dermatitis in some individuals.
4.2 Risk of systemic toxicity
Repeated oral administration of retinyl acetate has been shown to be toxic in animals. Female rats administered single equimolar oral doses of retinyl acetate in corn oil did not experience any toxic effects, but dietary supplementation with 250 mg retinyl acetate induced a low incidence of hepatic fibrosis after 120 and 180 days. Male rats fed an experimental diet containing 0.5% retinyl acetate for 7 days also had decreased food consumption, reduced body weight and other toxic syndromes. Monkeys in captivity which consumed a diet containing 45 nmol retinyl acetate/g dry food for 2 years presented with hypertrophy and hyperplasia of hepatic stellate cells in conjunction with elevated hepatic vitamin A concentrations, which are considered evidence of toxicity. In mice, retinyl acetate induced a significantly higher incidence of arthritis when included in the diet.
Although topical retinyl palmitate does not typically penetrate through the skin, delivery of retinyl palmitate to the dermis layer of the skin has been achieved through the use of proper polymeric nanoparticle carriers. Given that the dermis is usually vascularized, it stands to reason that retinyl palmitate released from such carriers may reach the systemic circulation, though whether the amount of systemic exposure achieved via this route is sufficient to induce systemic side effects is open to question.
4.3 Reproductive and developmental toxicity
Systemic retinyl acetate can adversely affect the reproductive ability of animals. Newly weaned male and female rats maintained on a vitamin A deficient diet but supplemented daily with 1 µg retinyl acetate for 18-22 weeks had reduced reproductive performance due to gestation resorption and sterility.
Oral doses of retinyl acetate can also be teratogenic and lethal to embryos, though less so than tretinoin or isotretinoin. Oral administration of 25,000 to 100,000 IU/kg retinyl acetate to pregnant female rats delayed the development of their pups, while pregnant mice dosed with moderate or high amounts of retinyl acetate had higher resorption rates and fetal malformations/abnormalities. Likewise, chronic ingestion of excessive amounts of retinyl acetate by female cats has the potential to cause birth defects in kittens.
4.4 Possible carcinogenicity
Studies thus far have demonstrated both the pro-carcinogenic and anticarcinogenic activities of retinyl acetate.
Oral administration of retinyl acetate has been shown to be correlated with a higher incidence of hormone- or chemically-induced mammary tumours in mice and rats as well as tumours of the adrenal medulla in male and female rats. It has also been reported as a co-carcinogen when co-administered with butylated hydroxyanisole in male rats.
Paradoxically, however, retinyl acetate has also been shown to be associated with inhibition of mammary tumour incidence and multiplicity in rats (but not mice), inhibition of the formation of squamous cell tumours in the urinary bladders of mice.^title=Retinyl acetate prophylaxis in cancer of the urinary bladder.] and delayed tumour induction by a carcinogen in hamsters.
It is possible that these contrasting results are due to different experimental conditions, the different species/strains of animals used, the different doses of retinyl acetate given and the different timeframes chosen.
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